The immediate goal of this proposal is to understand the mechanism for manganese (Mn) transport into the brain. Mn neurotoxicity is well established, and is an increasingly important problem in certain patient populations: those receiving parenteral nutrition, and those with chronic liver disease. Knowledge of factors influencing Mn accumulation in the brain will help in prevention of neurotoxicity. Also needed are biomarkers of Mn accumulation and effective treatment strategies. An established major factor which influences Mn accumulation is iron status. The role of iron transport proteins such as transferrin in mobilizing Mn is controversial. To address the relationship between iron status and Mn transport and the role of transferrin, studies are proposed using mutant hypotransferrinemic mice and dietary iron deficiency. This model provides the unique opportunity to control transferrin concentrations to determine the role of transferrin in Mn transport. The second line of research will address brain Mn deposition in animal models relevant to cholestatic liver disease. Studies are proposed using bile duct-ligated and portacavally- shunted rats. The third aim of this project is to evaluate MRI as a non invasive biomarker of Mn accumulation over time and with chelating agents. MRI will be related to chemical determination of Mn in tissues of mice. The results of the proposed studies should provide novel insights into mechanisms of Mn accumulation in and removal from the brain.